PRECOGx: e<b>x</b>ploring GPCR signaling mechanisms with deep protein representations

Matic, Marin; Singh, Gurdeep; Carli, Francesco; Rosa, Natalia De Oliveira; Miglionico, Pasquale; Magni, Lorenzo; Gutkind, J. Silvio; Russell, Robert B.; Inoue, Asuka; Raimondi, Francesco

doi:10.1093/nar/gkac426

Cited by 10 publications

(10 citation statements)

References 43 publications

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“…We generated G protein specific gene set as well as annotations by gathering consensus experimental transducer data (i.e., Universal Coupling Map 9 ) as well as predicted through Precogx 7 .…”

Section: Methodsmentioning

confidence: 99%

“…Systematic efforts are being undertaken to illuminate the complex circuitry of GPCR signaling at both the intracellular [5][6][7][8][9][10] as well as the extracellular ligand level 11 .…”

Section: Introductionmentioning

confidence: 99%

“…The GPCRs repertoire expanded and diversified to meet the increasing need for inter-cellular communication in evolving multicellular organisms 4,5 . Systematic efforts are being undertaken to illuminate the complex circuitry of GPCR signaling both at the intracellular [5][6][7][8][9][10][11] as well as the extracellular ligand level 12 .…”

Section: Introductionmentioning

confidence: 99%

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The landscape of cancer rewired GPCR signaling axes

Raimondi

Arora

Matic

et al. 2023

Preprint

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We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets. We derived a network of interacting ligands and biosynthetic enzymes from public databases, that we combined with cognate GPCRs and downstream effectors to quantify GPCR signaling pathways. We found multiple GPCRs differentially regulated together with their ligands across cancers, suggesting a widespread perturbation of these signaling axes in specific cancer molecular subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulates pathway activity signatures from metabolomics datasets, therefore providing valuable surrogate information for receptor-organic ligand systems. The expression of several GPCRs signaling components is significantly associated with either lower or higher patient survival in a cancer subtype specific fashion. In particular, the expression of both receptor-ligand (or biosynthetic enzyme) interaction partners improves the stratification of patients based on survival, suggesting a potential synergistic role for the activation of certain receptor axes in modulating cancer phenotypes. Strikingly, we have found that receptors from these actionable axes are the targets of several drugs displaying anti-growth effects in large, drug repurposing screens in cancer cell lines. This study provides a comprehensive map to exploit GPCR signaling axes as actionable targets for personalized cancer treatments. We have made the results generated in this study freely available for further exploration to the community through a webapp (gpcrcanceraxes.bioinfolab.sns.it).

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Section: Methodsmentioning

confidence: 99%

“…Systematic efforts are being undertaken to illuminate the complex circuitry of GPCR signaling at both the intracellular [5][6][7][8][9][10] as well as the extracellular ligand level 11 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The landscape of cancer rewired GPCR signaling axes

Raimondi

Arora

Matic

et al. 2023

Preprint

Self Cite

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“…The binding activities of GPCRs for transducer proteins are being quantitatively screened via medium-throughput methodologies 14 – 17 . Based on binding profiling from these large-scale experimental assays, sequence-based machine learning for coupling specificity has been proposed 18 , 19 . Phylogenetic analysis of co-evolutionary patterns inferred from sequence alignments of GPCRs and G-proteins have also provided insights into the sequence determinants of coupling specificity, for the entire GPCR family 20 as well as for specific subfamilies 21 .…”

Section: Introductionmentioning

confidence: 99%

GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach

et al. 2023

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GPCRs are master regulators of cell signaling by transducing extracellular stimuli into the cell via selective coupling to intracellular G-proteins. Here we present a computational analysis of the structural determinants of G-protein-coupling repertoire of experimental and predicted 3D GPCR-G-protein complexes. Interface contact analysis recapitulates structural hallmarks associated with G-protein-coupling specificity, including TM5, TM6 and ICLs. We employ interface contacts as fingerprints to cluster Gs vs Gi complexes in an unsupervised fashion, suggesting that interface residues contribute to selective coupling. We experimentally confirm on a promiscuous receptor (CCKAR) that mutations of some of these specificity-determining positions bias the coupling selectivity. Interestingly, Gs-GPCR complexes have more conserved interfaces, while Gi/o proteins adopt a wider number of alternative docking poses, as assessed via structural alignments of representative 3D complexes. Binding energy calculations demonstrate that distinct structural properties of the complexes are associated to higher stability of Gs than Gi/o complexes. AlphaFold2 predictions of experimental binary complexes confirm several of these structural features and allow us to augment the structural coverage of poorly characterized complexes such as G12/13.

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“…On one hand, quantitative screening methodologies have been set up to systematically profile the binding activities of GPCRs for transducer proteins [14][15][16][17] . Based on these large scale experimental assays, sequence-based machine learning for coupling specificity have been proposed 18,19 .…”

mentioning

confidence: 99%

GPCRome-wide structural analysis of G-protein-coupling selectivity

Matic

Miglionico

Inoue

et al. 2022

Preprint

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We present a comprehensive computational analysis of available 3D GPCR-G-protein complexes to inspect the structural determinants of G-protein-coupling selectivity. Analysis of the residue contacts at interaction interfaces has revealed a network of secondary structure elements recapitulating known structural hallmarks determining G-protein-coupling specificity, including TM5, TM6 and ICLs. We coded interface contacts into generic-number fingerprints to reveal specific coupling-determinant positions. Clustering of Gs vs Gi complexes is best achieved when considering both GPCR and G-protein contacting residues rather than separated representations of the interaction partners, suggesting that coupling specificity emerges as contextual residue interactions at the interface. Interestingly, Gs-GPCR complexes contain a higher number of contacts than Gi/o-GPCR complexes, likely caused by overall higher conservation and structural constraint on the Gs interface. In contrast, Gi/o proteins adopt a wider number of alternative docking poses on cognate receptors, as assessed via structural alignments of representative 3D complexes. Furthermore, binding energy calculations demonstrate that distinct structural properties of the complexes contribute to higher stability of Gs than Gi/o complexes. AlphaFold2 predictions of experimental binary complexes confirmed several of these structural features and allowed us to augment the structural coverage of poorly characterized complexes (e.g. G12/13). We propose that the structural properties of different G-protein complexes, such as structural restraining of Gs compared to Gi/o ones, could be instrumental in fine-tuning their activation and downstream signaling mechanisms.

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PRECOGx: exploring GPCR signaling mechanisms with deep protein representations

Cited by 10 publications

References 43 publications

The landscape of cancer rewired GPCR signaling axes

The landscape of cancer rewired GPCR signaling axes

GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach

GPCRome-wide structural analysis of G-protein-coupling selectivity

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